_heat-shock response article_ch310

_heat-shock response article_ch310 - Cont ent s Previous...

Info iconThis preview shows pages 1–2. Sign up to view the full content.

View Full Document Right Arrow Icon
Contents Previous Next Chapter 310 The Heat-Shock Response: Sensing the Stress of Misfolded Proteins Richard I. Morimoto and Ellen A. A. Nollen Department of Biochemistry, Molecular Biology and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois Introduction The heat-shock response is an inducible molecular response to physiological, environmental, and biochemical stress conditions ( Fig. 1 ) that results in the elevated expression of heat-shock genes. These can be classified into four categories: (1) environmental stresses, such as heat shock, amino acid analogs, drugs, oxidative stress, toxic chemicals, heavy metals, and pharmacologically active small molecules; (2) nonstress conditions, such as the cell cycle, growth factors, serum stimulation, development, differentiation, and activation by certain oncogenes; (3) physiological stress and disease states, such as neuroendocrine hormones, tissue injury and repair, fever, inflammation, infection, ischemia and reperfusion, and cancer; and (4) diseases of protein aggregation, such as Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, and ALS. For each of these categories, the various conditions indicated are typically associated with the overexpression of one or more heat-shock proteins through activation of heat-shock factor (HSF) and the heat-shock response. Common to these stresses are challenges to protein homeostasis that influence folding, translocation, assembly, and degradation events. Consequently, an increased flux of non-native intermediates, if left unprotected, will have an increased propensity to misfold and self-associate to form protein aggregates and other toxic protein species. The heat-shock response, through the elevated synthesis of molecular chaperones and proteases, responds rapidly and precisely to the intensity and duration of specific environmental and physiological stress signals to reestablish protein homeostasis and prevent protein damage [ 1 , 2 , 3 , 4 ]. Transient exposure to intermediate elevated temperatures or lower levels of chemical and environmental stress has cytoprotective effects against sustained, normally lethal, exposures to stress [ 5 ]. This reveals a valuable survival strategy that “a little stress is good.” Transcriptional Regulation of the Heat-Shock Response The stress-induced regulation of the heat-shock response in vertebrates occurs by activation of a family of heat-shock transcription factors (HSFs) from an inert state under normal steady-state conditions to a transcriptionally competent DNA-binding state [ 6 , 7 , 8 , 9 ]. Four HSF genes (HSF1–4) are expressed in vertebrates whereas yeast, Caenorhabditis elegans , and Drosophila encode a single HSF [ 9 - 15 ] with a high degree of conservation in the helix–loop–helix DNA-binding domain [ 8 , 16 , 17 ], adjacent 80-amino-acid hydrophobic repeat (HR-A/B) necessary for trimer formation [ 12 , 18 , 19 ], the centrally localized negative regulatory domain, and the
Background image of page 1

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon
Image of page 2
This is the end of the preview. Sign up to access the rest of the document.

This note was uploaded on 12/30/2010 for the course PMI 285 taught by Professor Wu during the Winter '04 term at UC Davis.

Page1 / 3

_heat-shock response article_ch310 - Cont ent s Previous...

This preview shows document pages 1 - 2. Sign up to view the full document.

View Full Document Right Arrow Icon
Ask a homework question - tutors are online